Travel Medicine and Infectious Disease 54 (2023) 102598

Contents lists available at ScienceDirect

Travel Medicine and Infectious Disease

journal homepage: www.elsevier.com/locate/tmaid

Qdenga® - A promising dengue fever vaccine; can it be recommended to

non-immune travelers?
Martin Angelin a, 1, Jan Sjölin b, Fredrik Kahn c, 1, Anna Ljunghill Hedberg b, 1, Anja Rosdahl d, e, 1,
Paul Skorup b, 1, Simon Werner f, 1, Susanne Woxenius g, 1, Helena H. Askling h, i, 1, *
a
Department of Clinical Microbiology, Infectious Diseases, Umeå University, Sweden
b
Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Sweden
c
Department of Clinical Sciences, Division of Infection Medicine, Lund University, Sweden
d
School of Medical Sciences, Örebro University, Örebro, Sweden
e
Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden
f
Department of Infectious Diseases, Skåne University Hospital, Malmö, Region Skåne, Sweden
g
Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
h
Department of Medicine, Solna, Division of Infectious Diseases, Karolinska Institutet, Sweden
i
Academic Specialist Centre, Stockholm County Health Care Services, Region Stockholm, Sweden

A B S T R A C T

Qdenga® has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The
vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4–16-year old’s living in endemic areas. For individuals
16–60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the
approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

Half of the world’s population is living in areas where dengue fever is
present [1]. Asian countries are most affected, reporting approximately
70% of all cases [2]. Although most infections are asymptomatic or mild,
progress to severe dengue fever and death occurs. Dengue fever virus
(DENV) constitutes four main distinct serotypes (DENV1-4). Infection
with one serotype results in long term immunity against that specific
serotype but only short-lived immunity against the other serotypes. A
second dengue infection is a risk factor for severe disease, but this is not
the case for subsequent infections [3]. The reason for this is unclear but
it is commonly attributed to antibody dependent enhancement (ADE)
[4], where cross reacting antibodies, forms immune complexes, instead
of neutralizing the virus, resulting in increased viremia and a more se­
vere disease. This phenomenon is important to consider in dengue fever
vaccine development and any vaccine candidate should preferably
induce long term immunity against all four serotypes.
At present there are two live attenuated tetravalent vaccines tar­
geting DENV1-4, Dengvaxia® and Qdenga®. Dengvaxia® is based on a
yellow fever backbone and was introduced in 2015. Clinical studies
showed an efficacy against virologically confirmed dengue fever (VCD)
of 60% [5]. However, during the third year of follow up the risk for
hospitalized VCD was increased in the vaccine group for dengue naïve
younger children compared to the placebo group [6]. The vaccine is now
limited to individuals with previous dengue fever, and it is not available
in non-endemic countries. Qdenga® is based on a DENV2 backbone with
recombinant strains expressing surface proteins for DENV1, DENV3 and
DENV4. By using a backbone of DENV2 instead of yellow fever virus it
has the potential to stimulate a broader humoral and cell mediated
immunological reaction [7].
Qdenga® is administered as a subcutaneous injection, two doses
with 3 months interval. It is contraindicated in immunocompromised
individuals as well as in pregnant and breastfeeding women. It seems to
be well tolerated and no serious adverse events have been linked [8].
Co-administration with hepatitis A vaccine has been studied without
increase in side effects or impaired antibody response [9]. When
co-administered with yellow fever vaccine a lower level of neutralizing
antibodies against DENV1 was seen, the clinical significance of which is
unclear [10]. Efficacy of Qdenga® has mainly been studied in the TIDES
study [11] following around 20 000 children and adolescents in eight
countries in Latin America and Asia. Two thirds were vaccinated and
one third received placebo. In the first year following vaccination a

* Corresponding author. Department of Medicine, Solna, Division of Infectious Diseases, Karolinska Institutet, Sweden.
E-mail address: helena.hervius.askling@ki.se (H.H. Askling).
1
These authors constitute the Vaccine Expert Group of Swedish Society for Infectious Diseases Physicians.

https://doi.org/10.1016/j.tmaid.2023.102598
Received 18 May 2023; Accepted 1 June 2023
Available online 2 June 2023
1477-8939/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M. Angelin et al.
vaccine efficacy against VCD of 80% was seen and it was 95% in pre­
venting VCD requiring hospitalization. The efficacy against VCD was
highest against DENV2 (98%) and lowest against DENV3 (63%). No
effect against DENV4 could be demonstrated at this time point due to
few cases. The cumulative vaccine efficacy 4,5 years after vaccination
[7] was 59% in preventing VCD (43–82% depending on serotype, 49%
against DENV4) and 84% in preventing VCD requiring hospitalization.
Vaccine efficacy was superior in individuals previously infected with
dengue fever. The cumulative efficacy 4,5 years after vaccination
against VCD was 50% in dengue naïve individuals compared to 63% in
those with previous infection. Additionally, no protective effect against
VCD caused by DENV3 and DENV4 was seen in dengue naïve in­
dividuals. Booster studies are ongoing, a booster dose is probably
needed in dengue naïve individuals. Vaccine efficacy in the three
months between dose 1 and 2 in preventing VCD was 81% [11].
In the third year after the second vaccine dose a higher proportion of
vaccinees were hospitalized with VCD due to DENV3 compared to the
placebo group in dengue naïve individuals. The explanation given is that
there was a lower threshold for hospitalization due to VCD in Sri Lanka
compared to other study countries (shown through subgroup analysis)
and that Qdenga® fails to protect against DENV3 [7,12]. During the
following 1,5 years this phenomenon has not been seen [7].
Qdenga® induces antibody responses against all four serotypes of
varying levels, highest for DENV2. The neutralizing antibody levels are
higher in individuals with previous dengue fever compared to dengue
naïve. The levels remain above cut-off for seropositivity in most in­
dividuals for several years after vaccination [7]. There is unfortunately
no defined serological correlate of protection yet [13] and no such level
was found in studies on Qdenga® [7]. In individuals >16 years of age no
efficacy studies have been carried out and vaccination in individuals
>60 years has not been studied at all.
Since dengue fever is such a widespread disease many international
travelers will visit an endemic country, but the risk is very variable
between regions. Incidence data for the local population as well as for
international travelers are important tools in decision making but reli­
able and updated estimates might be difficult to find. An approximation
of the risk in European travelers visiting endemic areas between 2015
and 2019 put the travel related incidence at 2.8 per 100 000 travelers
[14]. The travel related risk is also affected by duration of trip, as well as
repeated travel, type of travel, frequency of outdoor activities, type of
accommodation and seasonality of mosquito density. Dengue outbreaks
at the travel destination are important to consider.
In summary Qdenga® showed a clear protective effect against
dengue fever in children and adolescents 4–16 years living in endemic
areas but dengue naïve individuals were not protected against DENV3
and DENV4 from vaccination. Comparable levels of neutralizing anti­
bodies were seen in individuals 17-60-compared to those in 4–16-year-
olds [15]. In EMA:s approval no upper age limit was set despite the
above lack of data. No indication of disease enhancement has been seen
in the TIDES study up until 4,5 years after the second vaccine dose.
Qdenga® will have a significant effect in preventing dengue fever in
endemic countries but how to use it as a travel vaccine in individuals
living in non-endemic countries require some considerations, as anti­
body levels and their neutralizing capability after several years without
exposure to dengue virus is not known. Is a previously vaccinated
dengue naïve traveler at increased risk for a more severe disease when
travelling after several years if not receiving a booster dose before the
trip? With ageing the immunosenescence affects the ability to respond to
vaccines in general and these elderly might therefore have a reduced
seroprotection after Qdenga®-vaccination. Furthermore, are older in­
dividuals, due to a weakened antibody response, at risk for disease
enhancement?
In Sweden, Qdenga is now available at private vaccination-
policlinics at a cost of around 200 Euro per dose. The national regula­
tory and public health authorities have no intention to guide the use of
this vaccine. Dengue fever is a notifiable disease according to the
2
Travel Medicine and Infectious Disease 54 (2023) 102598
Swedish Act of Communicable Diseases, however this only applies to
laboratory verified cases made while back home. In 2019, 235 cases of
imported dengue fever were reported with an incidence of 2.28/100 000
which was a record high notification. Swedes are frequent travelers to
dengue-endemic areas and there is already a demand and questions on
how and when to use the vaccine. Therefore the Vaccine Expert group of
the Swedish Society for Infectious Diseases Physicians have reviewed the
literature to guide and formulate recommendations on the use of
Qdenga® as a travel vaccine.
In these recommendations we propose an initial cautionary approach
due to the lack of data in dengue-naive adults and especially elderly.
• For travelers with previous known self-reported (hospitalized or
policlinic testing) dengue fever, vaccination is recommended before
travel to an endemic country.
• For dengue naïve travelers vaccination may be considered in in­
dividuals aged 4–16 years old irrespective of travel duration.
• For travelers aged 17–60 years old we recommend considering
vaccination only for longer trips and related to travel destination. We
have suggested a trip for more than six weeks to South-East Asia, a
region with among the highest global incidence of dengue fever, to
be used as a reference.
• Since Qdenga® has not yet been studied in individuals >60 years old,
we advise vaccination should be avoided in this group until data are
available.
Travelling after only one vaccine dose should be avoided if possible,
which is a challenge for most travelers coming with shorter notice for
travel medicine advice. It can be considered, especially in individuals
with previous dengue fever, given that they receive the second dose after
return. As far as we know our recommendations are more cautious than
in other non-endemic countries, especially regarding the upper age
limit, and should be continuously revised when more information and
experience become available.
Declaration of competing interest
No conflict of interest.
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